Current evidence on the beneficial HOPE-effect based on systematic reviews and meta-analyses in liver transplantation
Authors: Alessandro Parente, Daniele Dondossola, Philipp Dutkowski, Andrea Schlegel
Journal: Journal of Hepatology (2023)

Comparing hypothermic oxygenated and normothermic liver machine perfusion: Translation mattersJournal of HepatologyVol. 80Issue 4PreviewMachine perfusion (MP) is a compelling technique to facilitate the safe transplantation of extended-criteria donation (ECD) livers. As evidenced in the recent meta-analysis by Parente et al.,1 both main paradigms of clinical MP, hypothermic oxygenated perfusion (HOPE) and normothermic machine perfusion (NMP) were reinforced by several randomized-controlled trials (RCTs), demonstrating their clinical superiority to static cold storage (SCS). The authors conclude that comparative studies and longer follow-up data are required to facilitate the introduction of routine MP. Full-Text PDF Machine perfusion techniques for liver transplantation - A meta-analysis of the first seven randomized-controlled trialsJournal of HepatologyVol. 79Issue 5PreviewMachine perfusion is increasingly being tested in clinical transplantation. Despite this, the number of large prospective clinical trials remains limited. The aim of this study was to compare the impact of machine perfusion vs. static cold storage (SCS) on outcomes after liver transplantation. Full-Text PDF We thank Tang et al.1Tang G. Zhang L. Zhou R. Letter to the Editor: machine perfusion techniques for liver transplantation - a meta-analysis of the first seven randomized controlled trials.J Hepatol. 2023; https://doi.org/10.1016/J.JHEP.2023.07.032Abstract Full Text Full Text PDF Google Scholar for their commentary regarding our recent meta-analysis summarizing the results of the first seven randomized-controlled trials (RCTs) on the use of machine perfusion in liver transplantation.2Parente A. Tirotta F. Pini A. et al.Machine perfusion techniques for liver transplantation - a meta-analysis of the first seven randomized controlled trials.J Hepatol. 2023; https://doi.org/10.1016/J.JHEP.2023.05.027Abstract Full Text Full Text PDF Google Scholar The authors discuss a few methodological points and challenge some beneficial perfusion effects, which we address below. Tang et al. discuss the evaluation of complications first. To date, only one RCT was powered to assess the impact of HOPE on major complications (Clavien-Dindo [CD] grade ≥3a) after liver transplantation.3Schlegel A. Mueller M. Muller X. et al.A multicenter randomized-controlled trial of hypothermic oxygenated perfusion (HOPE) for human liver grafts before transplantation.J Hepatol. 2023; https://doi.org/10.1016/J.JHEP.2022.12.030Abstract Full Text Full Text PDF Google Scholar Three other RCTs reported overall or major complications as secondary endpoints with heterogenous criteria and cut-offs to define major complications (i.e., patients with CD grade ≥3a or ≥3b). Next, complications are either captured as the number of patients with the highest CD grade per study group (grade 1, 2, 3a, 3b, 4a, 4b or 5) or shown as the overall number of complication events within and comparing the different study groups. While counting only the highest complication in a liver recipient may result in an underreporting of the overall morbidity, the analysis of more than one complication may impose additional challenges with pooling of RCTs in meta-analyses. Such critical factors may be the reason why only a few of the currently available 12 meta-analyses were able to include the endpoint "major complication" (Table 1). The recent Cochrane-based meta-analysis by Tingle et al. evaluated serious adverse events instead and found a moderate reduction with HOPE, thereby supporting the findings in our analysis.2Parente A. Tirotta F. Pini A. et al.Machine perfusion techniques for liver transplantation - a meta-analysis of the first seven randomized controlled trials.J Hepatol. 2023; https://doi.org/10.1016/J.JHEP.2023.05.027Abstract Full Text Full Text PDF Google Scholar,4Tingle S.J. Dobbins J.J. Thompson E.R. et al.Machine perfusion in liver transplantation.Cochrane Database Syst Rev. 2023; 9: CD014685https://doi.org/10.1002/14651858.CD014685.PUB2Crossref PubMed Google ScholarTable 1Overview of available meta-analyses on the beneficial effect of machine perfusion on outcomes after human liver transplantation.Author, Year, CountryNo. of included studiesType of included studiesType of machine perfusionMethodology (No. of studies)Main findingsDiscussionReduction or improvementNo effectsTingle et al., 2023, UK4Tingle S.J. Dobbins J.J. Thompson E.R. et al.Machine perfusion in liver transplantation.Cochrane Database Syst Rev. 2023; 9: CD014685https://doi.org/10.1002/14651858.CD014685.PUB2Crossref PubMed Google Scholar7RCTs: 7HOPE/D-HOPE: 4NMP: 3Systematic review & meta-analysis (7) (Cochrane handbook)HOPE and NMP reduce EAD; HOPE reduces NAS in DCD; HOPE reduces serious adverse events and improves graft survival at 1 year; NMP improved utilization.NMP had no beneficial effect on other outcomes, often due to the lack of endpoints reported in studies.Low risk of bias on outcomes with HOPE. Uncertain with NMP. No RCTs with NRP available. No trial assessed quality of life.Tang et al., 2023, China5Tang G. Zhang L. Xia L. et al.Hypothermic oxygenated perfusion in liver transplantation: a meta-analysis of randomized controlled trials and matched studies.Int J Surg. 2023; https://doi.org/10.1097/JS9.0000000000000784Crossref Scopus (3) Google Scholar11RCTs: 5Cohort studies: 6HOPE/DHOPE:11Systematic review (35) & meta-analysis (11)HOPE reduces EAD, acute rejection, overall biliary and NAS, improves graft survival and retransplantation at 1 yearNo additional significant effects.HOPE is superior to SCS for 1-year outcomes. No longer follow up available.Liang et al., 2023, China6Liang A. Cheng W. Cao P. et al.Effects of machine perfusion strategies on different donor types in liver transplantation: a systematic review and meta-analysis.Int J Surg. 2023; https://doi.org/10.1097/JS9.0000000000000661Crossref Scopus (3) Google Scholar39RCTs: 9Cohort studies: 30HOPE/D-HOPE:14NMP: 16NRP: 10Systematic review (40) & meta-analysis (26)HOPE reduces EAD, PNF, acute rejection, NAS, complications, improves graft survival at 1 year. NMP reduces EAD, NAS and complications in ECD. NRP reduces risk of NAS and improves 1-year graft survivalNo effect of NMP on patient and graft survivalMore evidence regarding NMP with ECD livers is needed.Parente et al., 2023, Italy/US2Parente A. Tirotta F. Pini A. et al.Machine perfusion techniques for liver transplantation - a meta-analysis of the first seven randomized controlled trials.J Hepatol. 2023; https://doi.org/10.1016/J.JHEP.2023.05.027Abstract Full Text Full Text PDF Google Scholar7RCTs: 7HOPE/D-HOPE: 4NMP: 3Systematic review & meta-analysis (Cochrane handbook) (7)HOPE and NMP reduce EAD; HOPE reduces biliary & overall complications.HOPE improves graft survival and reduces retransplantation rates at 1 yearNMP had no effect on graft survival or retransplantationHOPE is superior to SCS for 1-year outcomes. Lack of longer follow up. No RCTs with NRP available.Maspero et al., 2023, Italy/US7Maspero M. Ali K. Cazzaniga B. et al.Acute rejection after liver transplantation with machine perfusion versus static cold storage: a systematic review and meta-analysis.Hepatology. 2023; https://doi.org/10.1097/HEP.0000000000000363Crossref Scopus (14) Google Scholar8RCTs: 2Cohort studies: 6HOPE/D-HOPE: 6NMP: 1NRP: 1Systematic review & meta-analysis (8)Machine perfusion (combined HOPE, NMP and NRP) and HOPE alone reduce acute cellular rejection.NMP and NRP had limited to no individual effect on ACREndpoint ACR mainly reported in studies with HOPE, endpoint frequently lacking with other perfusion techniques. Heterogenous cohort of studies of different quality.Mugaanyi et al., 2022, China8Mugaanyi J. Dai L. Lu C. et al.A meta-analysis and systematic review of normothermic and hypothermic machine perfusion in liver transplantation.J Clin Med. 2022; 12https://doi.org/10.3390/JCM12010235Crossref PubMed Google Scholar10RCTs: 2Cohort studies: 8HOPE: 5NMP: 5Systematic review & meta-analysis (10)HOPE reduces biliary complications and improved patient and graft survival.No additional effects of any NMP techniqueHeterogenous cohort of studies of different quality.Jakubauskas et al., 2022, Austria9Jakubauskas M. Jakubauskiene L. Leber B. et al.Machine perfusion in liver transplantation: a systematic review and meta-analysis.Visc Med. 2022; 38: 243-254https://doi.org/10.1159/000519788Crossref PubMed Scopus (6) Google Scholar15RCTs: 3Cohort studies: 12HOPE: 6D-HOPE: 3NMP: 6Systematic review (15) & meta-analysis (9)HOPE reduces the rate of EAD and NAS compared to SCS.Studies with NMP not included in meta-analysis.HOPE reduces the rate of EAD and non- anastomotic biliary strictures compared to SCS. Meta-analysis included only studies with HOPE. Heterogenous cohort of studies of different quality, therefore NMP studies not includedRamírez-Del Val et al., 2022, UK∗Ramírez-Del Val A et al., Does machine perfusion improve immediate and short-term outcomes by enhancing graft function and recipient recovery after liver transplantation? A systematic review of the literature, meta-analysis and expert panel recommendations, Clin Transplant. 2022 Oct;36(10):e14638. https://doi.org/10.1111/ctr.14638.38RCTs: 4Cohort studies: 34HOPE: 12NMP: 13NRP: 13Systematic review (38) & meta-analysis (28)HOPE, NMP, NRP reduce EAD. HOPE and NMP reduce PRS, hospital stay. NMP reduces ICU stay. HOPE reduces major complications.No effect of NRP on hospital stay. No effect of HOPE on ICU stay.Heterogenous cohort of studies of different qualityLiew et al., 2021, UKLiew B et al., Liver transplant outcomes after ex vivo machine perfusion: a meta-analysis, The British journal of surgery (2021) 108(12) 1409-1416.34RCTs: 3Cohort studies: 17HOPE: 9NMP: 6Systematic review (34) & meta-analysis (20)HOPE and NMP reduce EAD. HOPE reduces NAS, graft loss, hospital stay.NMP had no effect on hospital stay or graft survival.Heterogenous cohort of studies of different quality.Jia et al., 2020, China§Jia J et al., A Systematic Review and Meta-Analysis of Machine Perfusion vs. Static Cold Storage of Liver Allografts on Liver Transplantation Outcomes: The Future Direction of Graft Preservation, Front Med (Lausanne). 2020 May 12:7:135.https://doi.org/10.3389/fmed.2020.00135. eCollection 2020.12RCTs: 2Cohort studies: 10HOPE: 5NMP: 7Systematic review & meta-analysis (12)HOPE and NMP reduce EAD. HMP reduces biliary complications.NMP had no effect on biliary complications.MP is superior to SCS for short-term outcomes. Uncertain effect on longer follow-up. Heterogenous cohort of studies of different quality.Zhang et al., 2019, ChinaZhang Y et al., Hypothermic machine perfusion reduces the incidences of early allograft dysfunction and biliary complications and improves 1-year graft survival after human liver transplantation: A meta-analysis, Medicine (2019) 98(23) e16033-e16033.6Cohort studies: 6HOPE: 6Systematic review & meta-analysis (6)MP reduces EAD. and biliary complications, increase 1-year graft survivalNo effect of MP on hospital stay, PNF, vascular complicationsNo randomized controlled trials includedJiang et al., 2018, China#Jiang X et al., Optimizing Livers for Transplantation Using Machine Perfusion versus Cold Storage in Large Animal Studies and Human Studies: A Systematic Review and Meta-Analysis. BioMed research international (2018) 2018 918075.19RCTs: 1Cohort studies: 7Animal studies: 11HOPE: 7SNMP/NMP:12Systematic review & meta-analysis (19)HOPE reduced EAD and biliary complicationsNMP had no effect on biliary complicationsMP is superior to SCS for short-term outcomes. Heterogenous cohort of studies of different quality.ACR, acute cellular rejection; EAD, Early allograft dysfunction; ECD, Extended criteria donor; HOPE, hypothermic oxygenated perfusion; MP, Machine perfusion; NMP, normothermic machine perfusion; NAS, non-anastomotic strictures; NRP, normothermic regional perfusion, PRS, postreperfusion syndrome; RCT, randomized controlled trial; SCS, static cold storage; SNMP, subnormothermic machine perfusion.Overview on currently available systematic reviews and meta-analyses with HOPE presented between 2018 and 2023 that include human liver transplantation. Key points that will be addressed in the future are: the currently limited posttransplant follow up of mostly one year and the lack of endpoints uniformly reported by studies and RCTs. Endpoints such as ACR and overall complications are frequently not reported with NMP and NRP. Information regarding the benefit of these preservation techniques on such clinically relevant endpoints is therefore limited. In addition, more RCTs were published with HOPE or D-HOPE (compared to NMP) and none is currently available with NRP. Direct comparative RCTs including HOPE and NMP are currently ongoing and results are awaited.∗ Ramírez-Del Val A et al., Does machine perfusion improve immediate and short-term outcomes by enhancing graft function and recipient recovery after liver transplantation? A systematic review of the literature, meta-analysis and expert panel recommendations, Clin Transplant. 2022 Oct;36(10):e14638. https://doi.org/10.1111/ctr.14638.∗∗ Liew B et al., Liver transplant outcomes after ex vivo machine perfusion: a meta-analysis, The British journal of surgery (2021) 108(12) 1409-1416.§ Jia J et al., A Systematic Review and Meta-Analysis of Machine Perfusion vs. Static Cold Storage of Liver Allografts on Liver Transplantation Outcomes: The Future Direction of Graft Preservation, Front Med (Lausanne). 2020 May 12:7:135.https://doi.org/10.3389/fmed.2020.00135. eCollection 2020.§§ Zhang Y et al., Hypothermic machine perfusion reduces the incidences of early allograft dysfunction and biliary complications and improves 1-year graft survival after human liver transplantation: A meta-analysis, Medicine (2019) 98(23) e16033-e16033.# Jiang X et al., Optimizing Livers for Transplantation Using Machine Perfusion versus Cold Storage in Large Animal Studies and Human Studies: A Systematic Review and Meta-Analysis. BioMed research international (2018) 2018 918075. Open table in a new tab ACR, acute cellular rejection; EAD, Early allograft dysfunction; ECD, Extended criteria donor; HOPE, hypothermic oxygenated perfusion; MP, Machine perfusion; NMP, normothermic machine perfusion; NAS, non-anastomotic strictures; NRP, normothermic regional perfusion, PRS, postreperfusion syndrome; RCT, randomized controlled trial; SCS, static cold storage; SNMP, subnormothermic machine perfusion. Overview on currently available systematic reviews and meta-analyses with HOPE presented between 2018 and 2023 that include human liver transplantation. Key points that will be addressed in the future are: the currently limited posttransplant follow up of mostly one year and the lack of endpoints uniformly reported by studies and RCTs. Endpoints such as ACR and overall complications are frequently not reported with NMP and NRP. Information regarding the benefit of these preservation techniques on such clinically relevant endpoints is therefore limited. In addition, more RCTs were published with HOPE or D-HOPE (compared to NMP) and none is currently available with NRP. Direct comparative RCTs including HOPE and NMP are currently ongoing and results are awaited. Third, Tang et al. discuss the different categories and definitions of biliary complications in context of known challenges of pooled analyses.1Tang G. Zhang L. Zhou R. Letter to the Editor: machine perfusion techniques for liver transplantation - a meta-analysis of the first seven randomized controlled trials.J Hepatol. 2023; https://doi.org/10.1016/J.JHEP.2023.07.032Abstract Full Text Full Text PDF Google Scholar Ravaioli et al. summarized in their RCT the number of biliary complications as "biliary strictures", which included anastomotic biliary strictures but also events classified as "biliary other", which were interpreted as non-anastomotic biliary strictures (NAS). We have repeated the pooled analysis based on an updated definition of "biliary stricture" with the same results. NAS occurred in 3.6% (8/218) and 8.7% (19/218) of recipients comparing the HOPE and SCS cohorts, respectively (risk ratio 0.42, CI 95% 0.19–0.95, p = 0.04, I2 0%). These results were largely expected and are supported by nine other meta-analyses, including the one recently presented by Tang et al., showing a reduction of biliary complications and/or NAS by HOPE (Table 1).5Tang G. Zhang L. Xia L. et al.Hypothermic oxygenated perfusion in liver transplantation: a meta-analysis of randomized controlled trials and matched studies.Int J Surg. 2023; https://doi.org/10.1097/JS9.0000000000000784Crossref Scopus (3) Google Scholar In their letter, Tang et al. also comment on the follow-up duration in RCTs and the pooled assessment of retransplantation and graft survival, which were both significantly improved by HOPE in our meta-analysis, despite exclusion of one RCT with a shorter follow-up of 6 months.2Parente A. Tirotta F. Pini A. et al.Machine perfusion techniques for liver transplantation - a meta-analysis of the first seven randomized controlled trials.J Hepatol. 2023; https://doi.org/10.1016/J.JHEP.2023.05.027Abstract Full Text Full Text PDF Google Scholar The recent Cochrane review by Tingle et al., including all four HOPE-RCTs with 6- or 12-months' post-transplant observation, supported our analysis. HOPE treatment protected from graft loss with high certainty and a hazard ratio of 0.45 (95% CI 0.23 to 0.87) compared to SCS.4Tingle S.J. Dobbins J.J. Thompson E.R. et al.Machine perfusion in liver transplantation.Cochrane Database Syst Rev. 2023; 9: CD014685https://doi.org/10.1002/14651858.CD014685.PUB2Crossref PubMed Google Scholar In summary, 12 systematic reviews and meta-analyses are currently available and provide evidence on HOPE in clinical liver transplantation.2Parente A. Tirotta F. Pini A. et al.Machine perfusion techniques for liver transplantation - a meta-analysis of the first seven randomized controlled trials.J Hepatol. 2023; https://doi.org/10.1016/J.JHEP.2023.05.027Abstract Full Text Full Text PDF Google Scholar,4Tingle S.J. Dobbins J.J. Thompson E.R. et al.Machine perfusion in liver transplantation.Cochrane Database Syst Rev. 2023; 9: CD014685https://doi.org/10.1002/14651858.CD014685.PUB2Crossref PubMed Google Scholar, 5Tang G. Zhang L. Xia L. et al.Hypothermic oxygenated perfusion in liver transplantation: a meta-analysis of randomized controlled trials and matched studies.Int J Surg. 2023; https://doi.org/10.1097/JS9.0000000000000784Crossref Scopus (3) Google Scholar, 6Liang A. Cheng W. Cao P. et al.Effects of machine perfusion strategies on different donor types in liver transplantation: a systematic review and meta-analysis.Int J Surg. 2023; https://doi.org/10.1097/JS9.0000000000000661Crossref Scopus (3) Google Scholar, 7Maspero M. Ali K. Cazzaniga B. et al.Acute rejection after liver transplantation with machine perfusion versus static cold storage: a systematic review and meta-analysis.Hepatology. 2023; https://doi.org/10.1097/HEP.0000000000000363Crossref Scopus (14) Google Scholar, 8Mugaanyi J. Dai L. Lu C. et al.A meta-analysis and systematic review of normothermic and hypothermic machine perfusion in liver transplantation.J Clin Med. 2022; 12https://doi.org/10.3390/JCM12010235Crossref PubMed Google Scholar, 9Jakubauskas M. Jakubauskiene L. Leber B. et al.Machine perfusion in liver transplantation: a systematic review and meta-analysis.Visc Med. 2022; 38: 243-254https://doi.org/10.1159/000519788Crossref PubMed Scopus (6) Google Scholar With a higher number of RCTs such analyses have also gained robustness over the past 5 years. The overview in Table 1 does however unveil the various challenges with most study endpoints, their heterogenous definitions, cut-offs and the relatively short post-transplant follow-up. Future RCTs in the field should also compare different dynamic preservation techniques and continue to focus on post-transplant morbidity, also providing data on long-term outcomes beyond 1 year. Despite various regulatory and financial obstacles, the HOPE approach is increasingly considered as standard of care for livers in many countries in and outside Europe, and "real-world data" on the longer-term outcomes of1,500 transplantations with HOPE are currently awaited.10Flores Carvalho M. Boteon Y.L. Guarrera J.V. et al.Obstacles to implement machine perfusion technology in routine clinical practice of transplantation - why are we not there yet.Hepatology. 2023; https://doi.org/10.1097/HEP.0000000000000394Crossref PubMed Scopus (5) Google Scholar No specific funding was obtained for this article. The other authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. AP and AS conceptualized the study; AP and AS designed the article; AP and AS wrote the manuscript; all authors contributed and approved the manuscript. The following are the supplementary data to this article: Download .pdf (.29 MB) Help with pdf files Multimedia component 1